Urea derivatives and salts thereof

ABSTRACT

Urea derivatives of the general formula (I) ##STR1## and salts thereof, pharmaceutical compositions containing the same, and methods for producing the same are-disclosed. 
     The urea derivatives of the general formula (I) and salts thereof are novel compounds having the acyl-CoA cholesterol acyltransferase (ACAT) inhibiting activity.

RELATED APPLICATIONS

This application is a continuation of Ser. No. 07/953,755, filed Sep.29, 1992, now U.S. Pat. No. 5,258,405, which is a continuation of Ser.No. 07/831,871, filed Feb. 5, 1992, now abandoned, which in turn is acontinuation-in-part of Ser. No. 07/666,721, filed Mar. 8, 1991, nowabandoned.

FIELD OF THE INVENTION

The present invention relates to urea derivatives of the followinggeneral formula (I) and salts thereof, which are of value as drugs forthe treatment and prevention of various diseases related, particularlyto atherosclerosis. ##STR2## wherein R¹ represents a condensedcarbocyclic group containing at least 11 carbon atoms; R² represents acycloalkyl group which may optionally have bridgeheads; R³ represents aphenyl group which may optionally be substituted by one or moresubstituents selected from the group consisting of halogens, lower alkylgroups, amino, and mono- or di-lower alkylamino groups or atetrahydronaphthyl group; A represents a single bond or a straight-chainor branched alkylene group containing 1 to 6 carbon atoms. The presentinvention further relates to pharmaceutical compositions containing thecompound (I) or a pharmaceutically acceptable salt thereof, andprocesses for producing the compound (I) or a salt thereof.

BACKGROUND OF THE INVENTION

It is known that accumulation of cholesterol in the vascular system isan etiologic factor in various diseases such as coronary heart disease.Atherosclerosis, among them, is a form of arteriosclerosis which ischaracterized by the deposition of lipids, particularly cholesterolesters, on the walls, and the resulting thickening, of medium- andlarge-sized arteries.

It has recently been made clear that the production of such cholesterolester is catalyzed by acyl-CoA cholesterol acyltransferase (ACAT). Thus,the excessive accumulation of cholesterol ester on the arterial wall isrelated to an increase in the ACAT enzyme level. Therefore, it isthought that if the ACAT enzyme is successfully inhibited, theesterification reaction of cholesterol will be retarded and thedevelopment and progression of atheromatous lesions due to excessiveaccumulation of cholesterol ester on the arterial wall be successfullyprevented.

On the other hand, cholesterol in diets is absorbed as unesterifiedcholesterol, esterified by the action of ACAT in the body and releasedinto the bloodstream in the form of chylomicrons. Therefore, inhibitionof ACAT would suppress not only absorption of dietary cholesterol fromthe intestinal tract but also reabsorption of the cholesterol releasedinto the intestine.

GB-A-2 113 684 discloses a series of antiatherosclerotic agents whichare certain substituted urea and thiourea compounds havingACAT-inhibiting activity.

EP-A-0 335 375 also discloses a series of antihyperlipidemic andantiatherosclerotic agents which are certain substituted urea compoundshaving ACAT-inhibiting activity.

SUMMARY OF THE INVENTION

An object of the present invention is to provide urea derivatives of theabove general formula (I) and salts thereof.

Another object of the invention is to provide processes for producingthe urea derivatives of the general formula (I) and salts thereof.

Still another object of the invention is to provide pharmaceuticalcompositions containing a urea derivative of the general formula (I) ora pharmaceutically acceptable salt thereof.

The compounds (I) according to the present invention are structurallydifferent from the known compounds mentioned above and as has been fullydemonstrated in the comparative pharmacological investigations describedhereinafter, have markedly superior pharmacologic activity than any ofthe known compounds.

The compounds (I) according to the present invention is structurallycharacterized in that a urea derivative is directly attached to acondensed carbocyclic nucleus with or without interposition of analkylene group.

DETAILED DESCRIPTION OF THE INVENTION

Referring to the definitions of the general formula (I), the "condensedcarbocyclic group containing at least 11 carbon atoms" includes, amongothers, ##STR3## and the like.

The "cycloalkyl group which may optionally have bridgeheads" is acycloalkyl group containing 3 to 18 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, cyclododecyl, cyclotridecyl, cyclopentadecyl,adamantyl, norbornyl and so on, and more preferably includes cycloalkylgroups containing 6 to 10 carbon atoms.

Referring to the "phenyl group which may optionally be substituted byone or more substituents selected from the group consisting of halogens,lower alkyl groups, amino, and mono- or di-lower alkylamino groups", thehalogen may be chlorine, fluorine, bromine or iodine; the lower alkylgroup is a straight-chain or branched alkyl group containing 1 to 5carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl (amyl), isopentyl, tert-pentyl, neopentyl,1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, etc.; and the mono- ordi-lower alkylamino group may be an amino group substituted by one ortwo lower alkyl groups mentioned above.

One or more, whether the same or different, of these halogens and loweralkyl, amino, and mono- or di-lower alkylamino groups may be present onthe phenyl group.

Such substituted phenyl group includes, among others,2,4,6-trifluorophenyl, 2,6-dimethylphenyl, 2,6-diethylphenyl,2,4,6-trimethylphenyl, 2,4,6-triethylphenyl, 4-propylphenyl,2,6-diisopropylphenyl, 4-t-butylphenyl, 4-dimethylaminophenyl and thelike.

The compound of the general formula (I) may form salts, and such saltsare also included within the scope of the present invention. Among suchsalts are acid addition salts with inorganic acids, such as hydrochloricacid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid,phosphoric acid, etc., and acid addition salts with organic acids, suchas formic acid, acetic acid, oxalic acid, citric acid, succinic acid,fumaric acid, maleic acid, malic acid, tartaric acid, methanesulfonicacid, ethanesulfonic acid and so on.

As mentioned hereinbefore, the present invention also provides processesfor producing the compounds (I) and salts thereof. Some representativeprocesses are described below. ##STR4## In the above reaction formula,R¹, R², R³ and A are as defined above, X represents a halogen atom andR⁴ represents a phenyl group or a lower alkyl group.

The compound (I) can be prepared by reacting the compounds of thegeneral formulae (II), (III) and (IV) either concurrently or in anoptional order. Preferably, the compound (I) can be produced by reactingan amino compound of the general formula (IV) with a haloformic acidester of the general formula (III) and reacting the resulting carbamicester with a compound of the general formula (II).

The haloformic acid ester of the general formula (III) includes isobutylchloroformate, methyl chloroformate, methyl bromocarbonate, phenylchloroformate and the like. There are cases in which the reaction can beadvantageously hastened using a base such as potassium carbonate, sodiumcarbonate, sodium hydroxide, potassium hydroxide, triethylamine,N,N-dinethylaniline and the like.

The reaction solvent may be virtually any inert solvent, such asN,N-dimethylformamide, chloroform, benzene, toluene, xylene, dioxane,ether, tetrahydrofuran, chloroform, dichloromethane, dichloroethane andso on. In regard to reaction temperature, the reaction between aminocompound (IV) and haloformic acid ester (III) is conducted under coolingor at room temperature and the reaction between the resulting carbamicacid ester and compound (II) is conducted at room temperature or underwarming. ##STR5## In the above reaction formula, R¹, R², R³ and A are asdefined above.

The compound (I) according to the present invention can also be producedby reacting an amino compound of the general formula (II) with anisocyanate compound of the general formula (V). The isocyanate compound(V) is used generally in an equimolar amount with respect to theCompound (II).

This reaction is conducted in an inert solvent, such asN,N-dimethylformamide, pyridine, benzene, toluene, dioxane,tetrahydrofuran, ether, chloroform, dichloromethane, dichtoroethane,n-hexane, etc., at room temperature or with heating. ##STR6## In theabove reaction formula, R¹, R², R³ and A are as defined above, and Xrepresents a halogen atom.

The compound (I) of the present invention can also be produced byreacting an amino compound of the general formula (II) with a halogencompound of the general formula (VI).

This reaction is conducted by reacting amino compound (II) with halogencompound (VI) in equimolar proportions in an inert solvent such asN,N-dimethylformamide, benzene, toluene, dioxane, tetrahydrofuran,ether, chloroform, dichloromethane, dichloroethane, n-hexane and so on.The reaction temperature is suitably decided depending on the startingcompounds and the solvent used in the reaction, but the reaction isgenerally carried out at room temperature or under warming.

The resulting compound (I) of the present invention can be isolated andpurified in the free form or in the form of a salt thereof bysalt-forming or desalting in a conventional manner. The isolation andpurification procedure may involve extraction, crystallization,recrystallization, chromatography and/or other chemical processes whichare commonly employed.

The compounds (I) of the present invention and salts thereof inhibitACAT to thereby inhibit the accumulation of cholesterol ester in thesmooth muscle cells of the arterial wall. It also inhibits theabsorption of cholesterol from the intestinal tract and facilitates thecatabolism and excretion of cholesterol in the liver to thereby lowerblood cholesterol levels and reduce the accumulation and storage ofcholesterol ester in the arterial wall, which in turn inhibits theformation or progression of atherosclerotic lesions. These actions arenot seen in the conventional lipid-lowering agents.

The compounds (I) and salts thereof according to the present inventionhave been demonstrated by animal experiments to have excellent bloodtotal cholesterol and low-density lipoprotein (LDL) lowering effects andis useful in lowering lipids as well as in the prevention and treatmentof various diseases related to arteriosclerosis, such as cerebralinfarction, transient ischemic attack, angina pectoris, peripheralthrombus and arteriosclerotic obliterans.

The effects of the compound of the present invention have been confirmedin the following manner.

i) ACAT enzyme inhibiting activity:

Inhibitory action against acyl-CoA cholesterol acyltransferase (ACAT)activity in rabbit liver microsome

The rabbit liver microsome was prepared as an enzyme fraction accordingto the method of Heider (J. G. Heider et al., J. of Lipid Res., Vol. 24,1127-34 (1983)).

To the mixture of 0.154M phosphate buffer solution (pH 7.4), 2 mMdithiothreitol, 36 μM bovine serum albumin and 10-100 μg of microsomefraction was added liposome prepared by the method of Suckling (K. E.Suckling et al., FEBS Letters, Vol. 151, No. 111-116 (1983)) so that theproposition of liposome became 20% v/v. To the mixture was added 2% v/vof each concentration of test compound solution in dimethyl sulfoxideand the mixture was heated at 37° C. for 5 minutes. Then 36 μM oleoylCoA containing 1¹⁴ C-oleoyl CoA was added and the resultant mixture washeated at 37° C. for 10 minutes. The reaction was stopped by addingchloroform/methanol (=2/1). After stirring, cholesterol oleate extractedinto the chloroform layer was separated by thin layer chromatography andthe radioactivity was determined as ACAT activity. The results obtainedare shown in Table 1.

                  TABLE 1                                                         ______________________________________                                                         ACAT Inhibiting Activity                                     Test Compound    IC.sub.50 *                                                  ______________________________________                                        Compound of Example 1                                                                          7.3 × 10.sup.-8 M                                      Compound of Example 10                                                                         6.1 × 10.sup.-8 M                                      ______________________________________                                         *IC.sub.50 : 50% Inhibition Concentration                                

ii) Lipid-lowering activity:

Male Sprague-Dawley rats, 5 weeks of age, were fed with a dietcontaining 1.5% cholesterol and 0.5% bile acid for 7 days and during thelast 5 days, the compound (I) of this invention suspended in a 0.5%aqueous solution of methylcellulose was orally administered via sondeonce a day. Two hours after the last administration, blood samples werecollected under ether anesthesia for determination of serum totalcholesterol level and HDL-cholesterol level. The cholesterol level wasdetermined by the method of Siedel et al. (Siedel, J. et al., J. Clin.Chem. Clin. Biochem., 19,838 (1981)) and the HDL-cholesterol level wasdetermined by the method of Ishikawa et al. (Ishikawa, T. et al.,Lipids, 11, 628 (1976)). The results obtained are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                           % Reduction in                                                                Serum Total Cho-                                           Test Compound      lesterol ED.sub.50                                         ______________________________________                                        Compound of Example 1                                                                            3.8       mg/kg                                            Compound of Example 10                                                                           1.7       mg/kg                                            Compound of Example 212                                                                          249       mg/kg                                            in GB-A-2,113,684                                                             Compound of Example 1                                                                            514       mg/kg                                            in EP-A-0,335,375                                                             ______________________________________                                    

As mentioned hereinbefore, another object of the present invention is toprovide a pharmaceutical composition containing the compound (I) or asalt thereof.

Such pharmaceutical composition can be manufactured by formulating thecompound (I) or a salt thereof with the pharmaceutically acceptablecarrier, vehicle or excipient which is commonly employed in the art inaccordance with the established pharmaceutical manufacturing practice.

The pharmaceutical composition of the present invention can beadministered orally in such dosage forms as tablets, pills, capsules,granules, powders, solutions, etc., parenterally in the form of aninjectable preparation, or otherwise, for example in the form ofsuppositories. The dosage depends on the symptom, the age and sex of thepatient and other factors but generally the daily oral dose per adulthuman, for instance, is about 50 mg to about 500 mg, which can beadministered in a single dose or in 2 to 4 divided doses.

The following examples are further illustrative of the present inventionand should by no means be construed as defining the metes and bounds ofthe invention. In the examples, ¹ H-NMR stands for proton nuclearmagnetic resonance. spectrum, Mass for mass spectrum, and IR forinfrared absorption spectrum.

Reference Examples are also given hereinafter for describing theprocesses for production of the starting compounds used in the Examples.

REFERENCE EXAMPLE 1 N-Cycloheptyl-[(2-fluorenyl)methyl]amine ##STR7##

2-Formylfluorene (2.27 g, 11.7 mmol) and cycloheptylamine (1.39 g, 12.3mmol) were heated together at 120° C. for 14 hrs. After cooling, thereaction mixture was distilled under reduced pressure. Then, ethanol (30ml) and sodium borohydride (0.44 g, 11.7 mmol) were added to the residueand the mixture was stirred for 0.5 hr. The mixture was then dilutedwith water (100 ml) and extracted with chloroform (80 ml×2 times). Theorganic layer was dried over anhydrous magnesiumsulfate. The solvent wasthen distilled off under reduced pressure to give 3.15 g of a paleyellow solid residue.

¹ H-NMR (δ ppm, in deuteriochloroform) 2.70 (1H, m), 3.79 (2H, s), 3.83(2H, s) Mass m/z 291 (M⁺)

The following compounds were Synthesized in generally the same manner asabove.

REFERENCE EXAMPLE 2 N-Cycloheptyl-[(9-phenanthrenyl)methyl]amine##STR8##

¹ H-NMR (δ ppm, in deuteriochloroform) 2.84 (1H, m), 4.23 (2H, s), 8.65(2H, m)

REFERENCE EXAMPLE 3N-Cycloheptyl-(6,7,8,9-tetrahydro-5H-benzocyclohepten-yl) amine ##STR9##¹ H-NMR (δ ppm, in deuteriochloroform) 3.95 (1H, m), 4.92 (1H, m), 7.10(4H, m) REFERENCE EXAMPLE 4 N-Cycloheptyl-[(2-phenanthrenyl)methyl]amine##STR10##

2-Methylphenanthrene (2.00 g, 10.4 mmol) was brominated withN-bromosuccinimide (2.05 g, 11.5 mmol) and the product compound wasadded gradually to a suspension of cycloheptylamine (2.38 g, 21.0 mmol)and potassium carbonate (2.90 μg, 21.0 mmol) in dimethylformamide (20ml) with ice-cooling. The mixture was then stirred at room temperaturefor 16 hrs and, then, filtered and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give 2.11 g of a viscous liquid. ¹ H-NMR (δ ppm, indeuteriochloroform) 2.83 (2H, m), 4.02 (2H, s), 8.68 (2H, m)

The following compound was synthesized in generally the same manner asabove.

REFERENCE EXAMPLE 5 N-Cycloheptyl-[(1-phenanthrenyl)methyl]amine##STR11##

¹ H-NMR δ ppm, in deuteriochloroform) 2.83 (1H, m), 4.20 (2H, s), 8.62(2H, m) Mass m/z 303 (M⁺)

REFERENCE EXAMPLE 6 N-Cycloheptyl-2-fluoreneacetamide ##STR12##

In dimethylformamide (50 ml) was dissolved 2-fluoreneacetic acid (2.24g) followed by addition of 1-hydroxybenztriazole (2.0 g) and, then,dicyclohexylcarbodiimide (3.1 g) with constant stirring and ice-cooling.The mixture was further ,stirred at room temperature for 15 minutes.Cycloheptylamine (1.7 g) was then added under ice-cooling and themixture was stirred at room temperature for 8 hrs. The resulting solidwas filtered off and the filtrate was distilled under reduced pressure.The residue was extracted with 50 ml of chloroform and the extract waswashed with 1N aqueous sodium hydroxide solution, 1N hydrochloric acidand water in the order mentioned and dried over anhydrous magnesiumsulfate. The solvent was then distilled off under reduced pressure andthe residue was purified by silica gel column chromatography to give 2.1g of N-cycloheptyl-2-fluoreneacetamide as a solid.

¹ H-NMR (δ ppm, in deuteriochloroform) 3.61 (2H, s), 3.90 (2H, s)

REFERENCE EXAMPLE 7 2-Cycloheptylaminoethylfluorene ##STR13##

In dry tetrahydrofuran (30 ml) was dissolved2-cycloheptylcarbamoylmethylfluorene (1.9 g) followed by dropwiseaddition of borane-methyl sulfide complex (1.8 ml) with ice-cooling. Themixture was then refluxed for 4 hrs, at the end of which time methanol(0.72 ml) was added with ice-cooling. The mixture was stirred at roomtemperature for 30 minutes, followed by addition of concentratedhydrochloric acid (1.8 ml) with ice-cooling. The mixture was refluxedagain for 30 minutes. The reaction mixture was then cooled with ice andthe resulting solid was recovered by filtration and washed with ether.The solid matter thus obtained was dissolved in chloroform and thesolution was alkalinized with aqueous sodium hydroxide solution. Thechloroform layer was taken and dried and the solvent was distilled offunder reduced pressure to give 2-cycloheptylaminoethylfluorene (1.2 g).

¹ H-NMR (δ ppm, in deuteriochloroform) 2.88 (4H, s), 3.86 (2H, s)

REFERENCE EXAMPLE 8 N-Cycloheptyl-[(1-fluorenyl)methyl]amine ##STR14##

To N-cycloheptyl-1-fluorenecarboxamide (1.00 g, 3.28 mmol) was added a1M solution of borane-tetrahydrofuran complex in THF (13 ml, 13 mmol)and the mixture was heated at 60° C. for 7.5 hrs. To this reactionmixture were added methanol (0.4 ml) and concentrated hydrochloric acid(3 ml) and the mixture was heated at 60° C. for 0.5 hr. Then, 1N aqueoussodium hydroxide solution (50 ml) was added at room temperature and themixture was extracted with chloroform (80 ml×2 times). The organic layerwas taken, dried and concentrated. To the residue were added ether (30ml) and 4N hydrogen chloride in ethyl acetate (2 ml) and the resultingwhite solid was collected by filtration. This solid was dissolved inchloroform (80 ml) and washed with 1N aqueous sodium hydroxide solution(80 ml×1). The Organic layer was dried and concentrated to give 0.90 gof a pale yellow solid.

¹ H-NMR (δ ppm, in deuteriochloroform) 2.71 (1H, m), 3.84 (2H, s), 3.87(2H, s) Mass m/z 291 (M⁺)

The following compound was synthesized in generally the same manner asabove.

REFERENCE EXAMPLE 9 N-Cycloheptyl-[(4-fluorenyl)methyl)amine ##STR15##

¹ H-NMR (δ ppm, in deuteriochloroform) 2.86 (1H, m), 3.90 (2H, s), 4.20(2H, s)

REFERENCE EXAMPLE 10 N-Cycloheptyl-[(2-biphenylenyl)methyl]amine##STR16##

Biphenylenecarboxylic acid (1.00 g, 5.10 mmol) and a small amount ofdimethylformamide were heated in 10 ml of thionyl chloride at 80° C. for0.5 hr. After cooling, the solvent was distilled off. To the residue wasadded methylene chloride (30 ml), followed by gradual addition of asolution of cycloheptylamine (0.86 g, 7.6 mmol) and triethylamine (0.77g, 7.6 mmol) in methylene chloride (20 ml) with ice-cooling. The mixturewas stirred at room temperature for 1 hr, at the end of which timechloroform (50 ml) was added. The mixture was washed with water (50 ml),dried over anhydrous magnesium sulfate and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give 1.39 g of the amide as a white solid.

¹ H-NMR (δ ppm, in deuteriochloroform) 1.58 (10H, s), 4.10 (1H, m) Massm/z 291 (M⁺)

In a 1M solution of boran-tetrahydrofuran complex in THF (37 ml), 2.85 gof the above amide was heated at 65° C. for 8 hrs. To the solution wasadded methanol (1 ml) and concentrated hydrochloric acid (5 ml), thereaction mixture was further heated at 65° C. for 1 hr and diluted with1N aqueous sodium hydroxide solution (100 ml). The mixture was extractedwith chloroform (160 ml×2 times) and the extract was dried overanhydrous magnesium sulfate and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography to give 1.19 gof the amine compound.

¹ H-NMR (δ ppm, in deuteriochloroform) 2.88 (1H, m), 3.70 (2H, s)

REFERENCE EXAMPLE 11 N-(5,6,7,8-Tetrahydronaphthyl)-0-phenylcarbamate##STR17##

A solution of phenyl chloroformate (7.83 g, 50 mmol) in toluene (20 ml)was added gradually to a solution of 5,6,7,8-tetrahydronaphthylamine(7.36 g, 50 mmol) and triethylamine (6.07 g, 60 mmol) in toluene (100ml) under ice-cooling. The mixture was then stirred at room temperaturefor 1 hr, followed by addition of ethyl acetate (100 ml). The mixturewas washed with water (100 ml), dried over anhydrous magnesium sulfateand concentrated under reduced pressure. The residue was washed withhexane and the resulting white solid was collected by filtration to give8.08 g of the carbamate.

¹ H-NMR (δ ppm, in deuteriochloroform) 1.90 (4H, m), 2.70 (4H, m), 7.64(1H, d) Mass m/z 267 (M⁺)

REFERENCE EXAMPLE 12 N-Cycloheptyl-1-(2-fluorenyl)ethylamine ##STR18##

2-Acetylfluorene (4.17 g, 20 mmol) and cycloheptylamine (2.38 g, 21mmol) were heated together at 130° C. for 14 hrs and, then, distilledunder reduced pressure. To the residue were added ethanol (20 ml) andsodium borohydride (0.76 g, 20 mmol) and the mixture was stirred at roomtemperature overnight. The mixture was then diluted with water (100 ml)and extracted with chloroform (80 ml×2 times). The organic layer wasdried over anhydrous magnesium sulfate and concentrated. The residue wasthen purified by silica gel column chromatography to give 1.58 g of theamine compound.

¹ H-NMR (δ ppm, in deuteriochloroform) 2.52 (1H, m), 3.76 (2H, s)

The following compound was synthesized in generally the same manner asabove.

REFERENCE EXAMPLE 13 N-(Exo-2-norbornyl)-(9-phenanthrenyl)methylamine##STR19##

¹ H-NMR (δ ppm, in deuteriochloroform) 2.28 (2H, m), 2.77 (1H, m), 4.20(2H, m) Mass m/z 301 (M⁺)

EXAMPLE 11-Cycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,4,6-trimethylphenyl)urea##STR20##

A mixture of N-cycloheptyl-[(2-fluorenyl)methyl]amine (980 mg, 3.36mmol) and N-(2,4,6-trimethylphenyl)-o-phenylcarbamate (820 mg, 3.2 mmol)in toluene (10 ml) was refluxed for 15 hrs.

The reaction mixture was then diluted with toluene (50 ml) and washedwith 1N aqueous sodium hydroxide solution (50 ml×2 times).

The organic layer was dried over anhydrous. magnesium sulfate andconcentrated. From the residue was obtained 940 mg of a white solid.

m.p. 124°-126° C. ¹ H-NMR (δ ppm, in deuteriochloroform) 1.96 (6H, s),3.89 (2H, s), 4.58 (2H, s), 6.76 (2H, s) Elemental analysis (for C₃₁ H₃₆N₂ O) Found: C, 82.47%; H, 8.08%; N, 6.16% Calcd.: C, 82.26%; H, 8.02%;N, 6.19%

The following compounds were synthesized in generally the same manner asabove.

EXAMPLE 21-Cycloheptyl-1-(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-3-(2,4,6-trifluorophenyl)urea##STR21##

IR (cm⁻¹, KBr tablet) 1640, 1520, 1450, 1120 ¹ H-NMR (δ ppm, indeuteriochloroform) 4.43 (1H, m), 4.70 (1H, m), 6.67 (2H, m) Mass (FAB)m/z 431 (M⁺ +1)

EXAMPLE 31-Cycloheptyl-1-[(9-anthracenyl)methyl]-3-(2,4,6-trifluorophenyl)urea##STR22##

m.p. 175°-177° C. H-NMR (5 ppm, in deuteriochloroform) 3.21 (1H, m),5.67 (2H, s), 8.48 (.1H, s) Elemental analysis (for C₂₉ H₂₇ N₂ OF₃)Found: C, 73.07%; H, 5.81%; N, 5.83%, F, 11.97% Calcd.: C, 73.09%; H,5.71%; N, 5.88%; F, 11.96%

EXAMPLE 4 1-Cycloheptyl-1-(9-fluorenyl)-3-(2,4,6-trifluorophenyl)urea##STR23##

IR (cm⁻¹, KBr tablet) 1650, 1520, 1460, 1120

¹ H-NMR (δ ppm, in deuteriochloroform) 4.62 (1H, m), 4.77 (1H, m), 6.42(2H, m) Mass (FAB) m/z (M⁺ +1)

EXAMPLE 51-Cycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,4,6-trifluorophenyl)urea##STR24##

IR (cm⁻¹, KBr tablet) 1640, 1520, 1450, 1120 ¹ H-NMR (δ ppm, indeuteriochloroform) 3.85 (2H, s), 4.35 (1H, m), 4.55 (2H, s) 6.54 (2H,m) Mass (FAB) m/z 465 (M⁺ +1)

EXAMPLE 61-Cycloheptyl-1-[(9-phenanthrenyl)methyl]-3-(2,4,6-trifluorophenyl)urea##STR25##

IR (cm⁻¹, KBr tablet) 1640, 1520, 1450, 1120 ¹ H-NMR (δ ppm, indeuteriochloroform) 4.50 (1H, m), 4.85 (2H, d), 6.51 (2H, m), 8.60 (2H,m) Mass (FAB) m/z 477. (M⁺ +1)

EXAMPLE 71-Cycloheptyl-1-[(9-phenanthrenyl)methyl]-3-(4-propylphenyl)urea##STR26##

IR (cm⁻¹, KBr tablet) 1650, 1520, 1250, 750 ¹ H-NMR (δ ppm, indeuteriochloroform) 0.83 (3H, t), 2.42 (2H, t), 4.48 (1H, m), 4.88 (2H,s) Mass (FAB) m/z 465 (M⁺ +1)

EXAMPLE 8 1-Cycloheptyl-1-[(2-fluorenyl)methyl]-3-(4-t-butylphenyl)urea##STR27##

IR (cm⁻¹, KBr tablet) 1660, 1540, 1420, 1330 ¹ H-NMR (δ ppm, indeuteriochloroform) 1.23 (9H, s), 3.90 (2H, s), 4.54 (2H, s) Mass (FAB)m/z 467 (M⁺ +1)

EXAMPLE 91-Cycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,6-dimethylphenyl)urea##STR28##

IR (cm⁻¹, KBr tablet) 1650, 1510, 1470, 760 .sup. H-NMR (δ ppm, indeuteriochloroform) 2.00 (6H, s), 3.90 (2H, s), 4.60 (2H, s), 6.95 (3H,s) Elemental analysis (for C₃₀ H₃₄ N₂ O) Found: C, 82.18%; H, 7.94%; N,6.22% Calcd.: C, 82.15%, H, 7.81%; N, 6.39%

EXAMPLE 101-Cycloheptyl-1-[(9-phenanthrenyl)methyl]-3-(2,4,6-trimethylphenyl)urea##STR29##

m.p. 108°-110° C. ¹ H-NMR (δ ppm, in deuteriochloroform) 2.06 (6H, s),4.60 (1H, m), 5.00 (2H, s), 6.76 (2H, s) Elemental analysis (for C₃₂ H₃₆N₂ O) Found: C, 82.51%; H, 8.02%; N, 5.93% Calcd.: C, 82.72%; H, 7.81%;N, 6.03%

EXAMPLE 111-Cycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,6-diethylphenyl)urea##STR30##

m.p. 134°-135° C.

¹ H-NMR (δ ppm, in deuteriochloroform) 1.09 (6H, t), 2.50 (4H, q), 4.00(2H, s) 4.69 (2H, s) Elemental analysis (for C₃₂ H₃₈ N₂ O) Found: C,82.35%; H, 8.21%; N, 5.90% Calcd.: C, 82.36%; H, 8.21%; N, 6.00%

EXAMPLE 121-Cycloheptyl-1-[(2-fluorenyl)methyl]-3-(2,6-diisopropylphenyl)urea##STR31##

IR (cm⁻¹, KBr tablet) 1650, 1500, 1470, 1240 ¹ H-NMR (δ ppm, indeuteriochloroform) 2.98 (2H, m), 4.00 (2H, s), 4.70 (2H, s) Mass (FAB)495 (M+1)

EXAMPLE 131-Cycloheptyl-1-[(2-phenanthrenyl)methyl]-3-(2,4,6-trifluorophenyl)urea##STR32##

IR (cm⁻¹, KBr tablet) 1640, 1520, 1120, 750 ¹ H-NMR (δ ppm, indeuteriochloroform) 4.43 (1H, m), 4.74 (2H, s) 6.58 (2H, m) Mass (FAB)m/z 477 (M⁺ +1).

EXAMPLE 14 1-Cycloheptyl-1-[(2-phenanthrenyl)methyl]-3-(2,46-trimethylphenyl) urea ##STR33##

m.p. 120°-122° C. IR (cm⁻¹, KBr tablet) 1630, 1510, 1260, 810 ¹ H-NMR (δppm, in deuteriochloroform) 1.94 (6H, s), 4.70 (2H, s), 6.72 (2H, s)Mass (FAB)m/z 465 (M⁺ +1)

EXAMPLE 151-Cycloheptyl-1-[(1-phenanthrenyl)methyl]-3-(2,4,6-trimethylphenyl) urea##STR34##

m.p. 163°-165° C. ¹ H-NMR (5 ppm, in deuteriochloroform) 2.06 (6H, s),5.05 (2H, s), 6.77 (2H, s) Elemental analysis: (for C₃₂ H₃₆ N₂ O) Found:C, 82.54%; H, 7.97%; N, 5.86% Calcd.: C, 82.72%; H, 7.81%; N, 6.03%

EXAMPLE 161-Cycloheptyl-1-[(1-phenanthrenyl)methyl]-3-(2,4,6-trifluorophenyl)urea##STR35##

IR (cm⁻¹, KBr tablet) 1650, 1520, 1120, 750 ¹ H-NMR (δ ppm, indeuteriochloroform) 4.44 (1H, m), 5.05 (2H, s), 6.62 (2H, m) Mass (FAB)m/z 477 (M⁺ +1)

EXAMPLE 171-Cycloheptyl-[(1-fluorenyl)methyl]-3-(2,4,6-trimethylphenyl)urea##STR36##

m.p. 183°-184° C. ¹ H-NMR (δ ppm, in deuteriochloroform) 2.00 (6H, s),3.83 (2H, s), 4.58 (2H, s) Elemental analysis (for C₋ H₃ N₂ O) Found: C,82.01%; H, 8.06%; N, 6.25% Calcd.: C, 82.26%; H, 8.02%; N, 6.19%

EXAMPLE 181-Cycloheptyl-[(4-fluorenyl)methyl]-3-(2,4,6-trimethylphenyl)urea##STR37##

m.p. 133°-136° C. ¹ H-NMR (δ ppm, in deuteriochloroform) 2.04 (6H, s),3.95 (2H, s), 4.97 (2H, s) Elemental analysis (for C₃₁ H₃₆ N₂ O) Found:C, 82.02%; H, 8.14%; N, 5.94% Calcd.: C, 82.26%; H, 8.02%; N, 6.19%

EXAMPLE 191-Cycloheptyl-1-[(2-fluorenyl)ethyl]-3-(2,4,6-trimethylphenyl)urea##STR38##

IR (cm⁻¹, KBr tablet) 2936, 1632, 1494 ¹ H-NMR (δ ppm, indeuteriochloroform) 2.12 (6H, s), 2.22 (3H, s), 3.00 (2H, t), 3.52 (2H,t), 3.84 (2H, s) Mass (FAB) m/z 467 (M⁺ +1)

EXAMPLE 20 ##STR39##1-Cycloheptyl-1-[(2-fluorenyl)ethyl]-3-(2,4,6-trifluorophenyl)urea##STR40##

IR (cm⁻¹, KBr tablet) 1638, 1522, 1452, 1120, 1044 ¹ H-NMR (δ ppm, indeuteriochloroform) 3.00 (2H, t), 3.52 (2H, t), 3.84 (2H, s) Mass (FAB)m/z 479 (M⁺ +1)

EXAMPLE 21 1-Cycloheptyl-1-(6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl)-3-[p-(N,N-dimethylamino)phenyl]ureamonohydrochloride ##STR41##

N-Cycloheptyl-(6,7,8,9-tetrahydro-5H-benzocycloheptenyl)amine (0.8 g,3.1 mmol) and 4-(N,N-dimethyamino)phenylisocyanate (0.50 g, 3.1 mmol)was stirred in dichloromethane (10 ml) at room temperature for 18 hrs.The reaction mixture was then purified by silica gel columnchromatography. The resulting urea compound was treated withhydrochloric acid in ether to give 0.72 g of the above hydrochloridecompound.

IR (cm⁻¹, KBr tablet) 1660, 1520, 1320 ¹ H-NMR (δ ppm, indeuteriochloroform) 3.13 (6H, s), 4.40 (1H, m), 7.2-7.5 (8H, m) Mass(FAB) m/z 421 (M⁺ +1)

EXAMPLE 221-Cycloheptyl-1-[(2-biphenylenyl)methyl]-3-(2,4,6-trimethylphenyl)urea##STR42##

N-Cycloheptyl-(2-biphenylenyl)methylamine (1.10 g, 3.96 mmol) andN-(2,4,6-trimethylphenyl)-0-phenylcarbamate (0.77 g, 3.00 mmol) wasrefluxed in toluene (10 ml) for 24 hrs. The reaction mixture was thendiluted with toluene (50 ml), washed with 1N aqueous sodium hydroxidesolution (50 ml×2 times), dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give 0.83 g of the urea compound.

m.p. 123°-124° C. IR (cm⁻¹, KBr tablet) 1630, 1510, 740 ¹ H-NMR (δ ppm,in deuteriochloroform) 2.05 (6H, s), 2.20 (3H, s), 4.24 (2H, s) Mass(FAB) m/z 439 (M⁺ +1)

The following compounds were synthesized in generally the same manner asabove.

EXAMPLE 23 1-Cycloheptyl-1-[1-(2-fluorenyl)ethyl]-3-(2,4,6-trimethylphenyl)urea ##STR43##

IR (cm⁻¹, KBr tablet) 1650, 1500, 1240, 740 ¹ H-NMR (δ ppm, indeuteriochloroform) 2.03 (6H, s), 3.88 (2H, s) Mass (FAB)m/z 467 (M++1)

EXAMPLE 241-(Exo-2-norbornyl)-1-[(9-phenanthrenyl)methyl]-3-[1(5,6,7,8-tetrahydronaphthyl)]urea##STR44##

IR (cm⁻¹, KBr tablet) 1650, 1530, 1230, 750 ¹ H-NMR (δ ppm, indeuteriochloroform) 2.60 (2H, m), 5.14 (2H, s) Mass (FAB) m/z 475 (M⁺+1)

EXAMPLE 251-Cyclohexyl-1-[(9-phenanthrenyl)methyl]-3-(2,4,6-trifluorophenyl)urea##STR45##

A mixture of N-cyclohexyl-N-(9-phenanthrenyl-methyl)amine (0.90 g) andN-(2,4,6-trifluorophenyl)-o-phenylcarbamate (0.80 g) in toluene (10 ml)was refluxed for 17 hrs. After cooling, the reaction mixture was dilutedwith toluene (80 ml). The organic layer was washed with 1N aqueoussodium hydroxide solution-(80 ml×2 times), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas crystallized from hexane-ether, and the resulting solid wascollected by filtration and dried to give 1.01 g of1-cyclohexyl-1-[(9phenanthrenyl)methyl]-3-(2,4,6-trifluorophenyl)urea.

m.p. 122°-124° C. IR (cm⁻¹, KBr tablet) 3340, 1665, 1650, 1325, 1125,1045, 755 ¹ H-NMR (6 ppm, in deuteriochloroform) 0.9-2.0 (10H), 4.50(1H, m), 5.02 (2H, s), 5.76 (1H, s), 6.60 (2H, t), 7.6-8.1 (7H), 8.6-8.8(2H, m)

The following compounds were synthesized in generally the same manner asabove.

EXAMPLE 26 1-Cyclohexyl-1- [(9-phenanthrenyl)methyl]-3-(2,4,6-trimethylphenyl)urea ##STR46##

m.p. 125°-128° C. IR (cm⁻¹, KBr tablet) 3340, 1655, 1635, 1500, 1245,750 ¹ H-NMR (6 ppm, in deuteriochloroform) 0.9-2.0 (10H), 2.03 (6H, s),2.17 (3H, s), 4.54 (1H, m), 5.02 (2H, s), 5.64 (1H, s), 6.74 (2H, s),7.5-8.1 (7H, m), 8.6-8.8 (2H, m) Elemental analysis (for C₃₁ H₃₄ N₂ O)Found: C, 82.79%; H 7.75%; N, 6.21% Calcd.: C, 82.63%; H, 7.61%; N,6.22%

EXAMPLE 271-Cyclohexyl-1-[(2-fluorenyl)methyl]-3-(2,4,6-trifluorophenyl)urea##STR47##

m.p. 162°-165° C. IR (cm⁻¹, KBr tablet) 3250, 1640, 1530, 1460, 1125,1450, 840 ¹ H-NMR (6 ppm, in deuteriochloroform) 1.0-2.0 (10H, m), 3.90(2H, s), 4.34 (1H, m), 4.62 (2H, s), 5.64 (1H, s), 6.60 (2H, t) 7.2-7.8(7H, m,) Elemental analysis (for C₂₇ H₂₅ N₂ OF₃) Found: C, 72 02%; H, 572% N, 6 07% F 12.42% Calcd.: C, 71.99%; H, 5.59%; N, 6.22%; F, 12.65%

EXAMPLE 281-Cyclohexyl-1-[(2-fluorenyl)methyl]-3-(2,4,6trimethylphenyl)urea##STR48##

m. p. 147°-149° C. IR (cm⁻¹, KBr tablet) 3330, 1630, 1510, 1245, 765,735 ¹ H-NMR (6 ppm, in deuteriochloroform) 1.0-2.0 (10H, m), 1.95 (6H,s), 2.17 (3H, s), 3.87 (2H. s), 4.4O (1H, m), 4.57 (2H, s), 5.56 (1H,s), 6.76 (2H, s), 7.2-7.8 (7H, m) Elemental analysis (for C₃₀ H₃₄ N₂ O)Found: C, 82.09%; H, 7.87%; N, 6.30% Calcd.: C, 82.15%; H, 7.82L%; N,6.39%

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. An urea derivative of the formula (I): ##STR49##wherein R¹ represents a condensed carbocyclic group containing at least11 carbon atoms; R² represents a cycloalkyl group which may optionallyhave a bridgehead; R³ represents a phenyl group which may optionally besubstituted by one or more substituents selected from the groupconsisting of halogens, lower alkyl groups, amino, and mono- or di-loweralkylamino groups or a tetrahydronaphthyl group; A represents a singlebond or a straight-chain or branched alkylene group containing 1 to 6carbon atoms, or a salt thereof.
 2. An urea derivative or a salt thereofas claimed in claim 1, wherein R¹ in formula (I) is a fluorenyl group.3. An urea derivative or a salt thereof as claimed in claim 1, whereinR¹ in formula (I) is a phenanthrenyl group.
 4. An urea derivative or asalt thereof as claimed in claim 1, wherein R¹ in formula (I) is afluorenyl group and R³ in formula (I) is a phenyl group which issubstituted by three lower alkyl groups. 5.1-Cycloheptyl-1-(2-fluorenylmethyl)-3-(2,4,6-trimethylphenyl)urea or asalt thereof. 6.1-Cycloheptyl-1-(9-phenanthrenylmethyl)-3-(2,4,6-trimethylphenyl)urea ora salt thereof.
 7. A pharmaceutical composition comprising atherapeutically effective amount of an urea derivative of the formula(I) ##STR50## wherein R¹ represents a condensed carbocyclic groupcontaining at least 11 carbon atoms; R² represents a cycloalkyl groupwhich may optionally have a bridgehead; R³ represents a phenyl groupwhich may optionally be substituted by one or more substituents selectedfrom the group consisting of halogens, lower alkyl groups, amino, andmono- or di-lower alkylamino groups or a tetrahydronaphthyl group; Arepresents a single bond or a straight-chain or branched alkylene groupcontaining 1 to 6 carbon atoms, or a salt thereof, and apharmaceutically acceptable-carrier.
 8. The pharmaceutical compositionas claimed in claim 7, wherein R¹ in formula (I) is a fluorenyl group.9. The pharmaceutical composition as claimed in claim 7, wherein R¹ informula (I) is a phenanthrenyl group.
 10. The pharmaceutical compositionas claimed in claim 7, wherein R¹ in formula (I) is a fluorenyl groupand R³ in formula (I) is a phenyl group which is substituted by threelower alkyl groups.
 11. The pharmaceutical composition as claimed inclaim 8 wherein the urea derivative is1-Cyclohepthyl-1-(2-fluorenylmethyl)-3-(2,4,6-trimethylphenyl)urea or asalt thereof.
 12. The pharmaceutical composition as claimed in claim 9wherein the urea derivative is1-Cyclohepthyl-1-(9-phenanthrenylmethyl)-3(2,4,6-trimethylphenyl)urea ora salt thereof.